ABSTRACT Over 5 million Americans suffer from heart failure with over a half a million newly diagnosed cases each year. The annual cost of treatment is approaching 40 billion dollars with over 20 billion dollars in hospital expenses alone. The incidence of heart failure increases with age and is markedly higher amongst minority populations. Therefore, heart failure presents a major health problem in the United States as well as worldwide. Exercise intolerance is a classic symptom of heart failure. Even moderate exercise may leave the patient exhausted and out of breath. Often extreme activation of the sympathetic nervous system occurs during exercise causing profound peripheral vasoconstriction. High sympathetic activity is predictive of poor prognosis in heart failure. Our recent studies have shown that even the heart and skeletal muscle become targets for vasoconstriction with this veritable ?sympathetic storm?. The mechanisms mediating this exaggerated activation of the sympathetic nervous system during exercise in subjects with heart failure are poorly understood. This competing renewal proposal is focused on expanding our investigations of altered neural control of cardiovascular function during exercise in heart failure. We propose that sympathetic over- activation during exercise stems from underperfused skeletal muscle causing excessive excitation of the muscle metaboreflex raising sympathetic activity. This increased sympathetic tone is amplified via positive feedback reflexes stemming from vasoconstriction in the ischemic muscle itself causing more metaboreflex activation as well as vasoconstriction in the coronary vasculature causing over-excitation of the cardiac sympathetic afferent reflex (CSAR) eliciting even further sympatho-activation. Altered arterial baroreflex buffering of these positive feedback scenarios arising from the muscle metaboreflex and CSAR contributes to the excessive sympatho-activation. We will utilize our innovative and highly complex conscious, chronically instrumented canine model. Our long term goal is to further elucidate the mechanisms responsible for the heightened activation of the sympathetic nervous system during exercise in heart failure and the functional consequences of these responses in integrative control of cardiovascular function. A major strength of the proposal is our unique capability of simultaneous measurement of critical central and peripheral hemodynamic parameters in real time at rest and during exercise in the same animals before and after induction of heart failure. These longitudinally designed experiments will provide compelling new information on the altered mechanisms of cardiovascular control during exercise in heart failure and may provide a basis for ameliorating the excessive activation of the sympathetic nervous system during exercise in these patients.